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In 1957, the first results from a clinical trial of the diabetes drug metformin in patients were published. Yet, it would take nearly 40 years for the drug to be approved in the United States as a treatment for type 2 diabetes.

Now researchers want to know whether this decades-old drug may have additional uses in another disease—cancer. Based on findings from a number of large epidemiologic studies and extensive laboratory research, metformin is being tested in clinical trials not only as a treatment for cancer, but as a way to prevent it in people at increased risk, including cancer survivors who have a higher risk of a second primary cancer.

Some of the early-phase prevention trials of metformin are enrolling participants who are at increased risk for cancer and who are obese, have elevated glucose or insulin levels, or have other conditions that put them at risk for diabetes.

“With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population,” said Brandy Heckman-Stoddard, PhD, MPH, of NCI’s Division of Cancer Prevention.

Expanding the Data Pool

Much of the human data on metformin and cancer has come from epidemiologic studies of people with diabetes. In many, though not all, of these studies, people with diabetes who were assigned to take metformin had a lower incidence of cancer than those taking other diabetes drugs.

Completed in 2002, the original DPP enrolled more than 3,200 people at increased risk of developing diabetes and randomly assigned them to one of three groups: one group received metformin, one took part in an intensive diet and physical activity program, and one received a placebo. Participants in the metformin arm had a substantially lower risk of developing diabetes than the general population; participants in the exercise and diet regimen fared even better.

With NCI’s involvement, the program’s extension, called the DPP Outcomes Study, will allow investigators to document cancer incidence and death among study participants. Those observations should provide some of the strongest data available to date on metformin’s anticancer effects in people without diabetes, explained Dr. Heckman-Stoddard. The first data on cancer outcomes in study participants, which will be based on 15 years of follow-up, should be available in 2014.

“Once we have that data, there are a host of other questions we can ask,” she said. For example, Dr. Heckman-Stoddard and her colleagues plan to study metformin’s impact on certain blood biomarkers that studies have suggested are associated with cancer risk. They will also study the drug’s mechanism of action—that is, how metformin may work to prevent changes in cells that can lead to cancer.

For Prevention, Small Biomarker-Driven Trials

The smaller prevention trials being conducted are very different from the DPP Outcomes Study. These trials are not designed to determine whether metformin prevents cancer. Prevention trials must generally have a large number of participants and span many years to show whether a drug or some other intervention reduces the risk of cancer.

Instead, these short, 3- to 6-month trials are investigating whether the drug has an effect on specific proteins and/or signaling pathways that have been implicated in cancer development and that laboratory studies have shown are affected by metformin.

At the University of California, Irvine Chao Family Comprehensive Cancer Center, for example, Jason Zell, DO, MPH, is leading an early-phase clinical trial that is testing metformin’s effect on the mTOR signaling pathway in obese people who have previously had precancerous growths removed from their colons.

Numerous studies have implicated the mTOR pathway as an integral hub in cancer development and progression, and laboratory studies have consistently shown that metformin can blunt mTOR signaling.

“The key point of the trial is to get at the mechanisms of action … to see if metformin is behaving in the expected manner” based on the lab findings, Dr. Zell explained.

Numerous early-stage clinical trials are currently under way to investigate metformin's potential to prevent an array of cancers, including colorectal, prostate, endometrial, and breast cancer.

Dr. Zell and his colleagues chose to study obese patients “because of the interesting side-effect profile of metformin, which can include weight loss,” meaning it may not be suitable for underweight, nondiabetic individuals, he continued.

If this first trial shows that metformin is having the expected effects on mTOR signaling, the next trial would be similar but would measure a clinical outcome, such as whether metformin decreases the number of colorectal polyps that return.

A phase II trial at the University of California, San Diego Moores Cancer Center is testing metformin’s effects on a host of biomarkers in postmenopausal breast cancer survivors who are obese.

Funded by NCI’s Transdisciplinary Research on Energetics and Cancer (TREC) program, the trial, called Reach for Health, will involve treatment with metformin alone and in combination with an exercise program. The study will examine the effect of 6 months of metformin treatment, with or without exercise, on a host of biomarkers associated with cancer risk. The change in biomarker measurements before and after treatment will be compiled into a score that predicts the risk of dying from breast cancer.

This is all part of the trial’s novel “biomarker bridge” design, the lead investigator, Ruth Patterson, PhD, explained. The biomarkers and the risk score are being derived from an analysis of tissue samples collected as part of an NCI-supported phase III trial called the Women’s Healthy Eating and Living (WHEL) study. This study found that a diet low in fat and high in fruits and vegetables did not reduce the risk of cancer returning in survivors of early-stage breast cancer compared with survivors who maintained their normal diet. Researchers have continued to follow the health of WHEL participants to document their health outcomes, including death from breast cancer.

“The WHEL trial is over, and we have a freezer full of blood samples, and we know participants’ breast cancer recurrences, mortality, and other outcomes,” Dr. Patterson said. “So we’re hooking together a short-term trial with a long-term cohort study by means of blood biomarkers.”

The Dose Is the Question

Most of the cancer clinical trials of metformin use the same doses typically used to treat diabetes. That makes sense, because all of the epidemiologic data suggesting a cancer benefit came from studies that used those doses, said Michael Pollak, MD, of McGill University in Montreal, who has extensively studied metformin and its anticancer potential.

“We already know that those doses are safe, so why not study them?” Dr. Pollak continued. “But then you have to realize that virtually all of the lab studies [of metformin] have been done using drug concentrations that are as much as 100-fold higher than those found in the serum of diabetic patients. So the lab studies do not directly justify the clinical trials that are using conventional antidiabetic doses.”

With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population.

—Dr. Brandy Heckman-Stoddard

Although laboratory studies suggest that larger doses of metformin “deserve study” for cancer treatment, Dr. Pollak noted that “for cancer prevention, we can only consider the hypothesis that the antidiabetic dose, or even lower doses, will be clinically useful.”

Dr. Zell agreed. “In the realm of cancer prevention, where side effects are less acceptable than they are in the realm of cancer treatment, the conventional dose for treating diabetes or something close to it may be the limit.

“I don’t imagine that prevention researchers will be looking to use [significantly larger] doses of metformin,” he continued. “In a healthy population, even a low risk of side effects could be extraordinary when applied to a larger population…. That’s why trials like ours are important. At the end of this 12-week intervention, we’ll have a good idea of whether the standard dose of metformin can affect cancer signaling pathways.”

Early Days

It’s still far too early to tell whether there is any future for metformin as a means of preventing or treating cancer, several researchers said.

Despite the very strong epidemiological evidence, there’s a chance that, even if metformin has some ability to prevent cancer, its efficacy may be limited to just several cancer types, Dr. Pollak noted. For example, metformin is not absorbed very well by the body and is absorbed differently by different tissues, he explained, which could limit how effective it might be against particular cancers.

Although the drug in its current form has certain limitations, some investigators are working on developing more potent derivatives of metformin. At the 2012 San Antonio Breast Cancer Symposium, for example, Italian and U.S. researchers reported that several metformin derivatives they had developed potently blocked the growth of breast cancer cells in the laboratory, including cell lines of triple-negative breast cancer, and caused the cells to die.

To be used for cancer prevention, any metformin derivative would have to be safe, with few side effects, Dr. Heckman-Stoddard stressed. As for the original metformin formulation, she added, current trials should help to map the way forward for its use in prevention.

“It’s important that we identify the right populations in which this is most likely to be an effective agent,” said Dr. Heckman-Stoddard. “We need to look at the evidence from all of these early-phase trials as a whole,” she continued, including examining the population groups exhibiting the strongest suggestions of efficacy “so we can design efficient phase III trials.”

Changes in the levels of the signaling pathway protein pS6K1, thought to play important role in progression to esophageal cancer

Mayo Clinic

Posted: April
15, 2013

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